Use of a histamine antagonist, an interleukin-1 antagonist and/or a TNF αantagonist in a cosmetic, pharmaceutical or dermatological composition and composition obtained

ABSTRACT

The invention relates to the use of a histamine antagonist, an interleukin-1 antagonist and/or a TNF alpha antagonist in a cosmetic, pharmaceutical or dermatological composition for treating sensitive skins. It relates especially to the use of a histamine antagonist, an interleukin-1 antagonist and/or a TNF alpha antagonist for preventing and/or combating skin irritations and/or sores and/or erythema and/or dysaesthetic sensations and/or sensations of inflammation and/or pruritus and/or prickling and/or tingling and/or discomfort and/or tightness of the skin and/or mucosae. It also relates to a composition containing a histamine antagonist, an interleukin-1 antagonist and/or a TNF alpha antagonist which limits or eliminates the irritant side-effects of certain products, and in particular of certain cosmetic, dermatological or pharmaceutical active agents.

This application is a continuation, of application Ser. No. 08/879,889,filed Jun. 20, 1997 now U.S. Pat. No. 5,993,833; which is turn is adivisional of application Ser. No. 08/580,291, filed Dec. 28, 1995 nowU.S. Pat. No. 5,658,581.

The present invention relates to the use of a histamine antagonist, aninterleukin-1 antagonist and/or a TNF alpha antagonist in a cosmetic,pharmaceutical or dermatological composition for topical application,intended, in particular, for the treatment of sensitive skins, as wellas to a composition containing a histamine antagonist, an interleukin-1antagonist and/or a TNF alpha antagonist for the purpose of decreasingor even abolishing the irritant effects of certain products, and inparticular of certain active agents used in the cosmetics,pharmaceutical or dermatological field.

It is known that some skins are more sensitive than others. The symptomsof sensitive skin were hitherto poorly characterized and the problem ofthese skins was, as a result, poorly defined; nobody understoodprecisely the process involved in sensitivity—non-allergic cutaneoushyperreactivity—of the skin. Some workers believed that a sensitive skinwas a skin which reacted to cosmetic products, others that such a skinwas one which reacted to several external factors, not necessarilyassociated with cosmetic products.

Some tests have been tried in an effort to pinpoint sensitive skins, forexample tests involving lactic acid and DMSO, which are known to beirritant substances: see, for example, the paper by K. Lammintausta etal., Dermatoses, 1988, 36, pages 45-49; and the paper by T. Agner and J.Scrup, Clinical and Experimental Dermatology, 1989, 14, pages 214-217.However, these tests did not enable sensitive skins to be characterizedcompletely.

Moreover, sensitive skins were likened to allergic skins.

Since the characteristics of sensitive skins were poorly understood, itwas very difficult to treat them hitherto, and they were treatedindirectly, for example by limiting the use of products having anirritant character, such as surfactants, preservatives or perfumes aswell as certain active agents, in cosmetic or dermatologicalcompositions.

The Applicant has carried out numerous clinical tests and has been ableto determine the symptoms associated with sensitive skins. Thesesymptoms are, in particular, subjective signs which are essentiallydysaesthetic sensations. Dysaesthetic sensations are understood to meanmore or less painful sensations experienced in an area of the skin, suchas prickling, tingling, itching or pruritus, burning, inflammation,discomfort, tightness, and the like.

The Applicant was able to show, in addition, that a sensitive skin wasnot an allergic skin. In effect, an allergic skin is a skin which reactsto an external agent, an allergen, which triggers an allergic reaction.This is an immunological process which takes place only when an allergenis present and which affects only sensitized subjects. The essentialcharacteristic of sensitive skin is, according to the Applicant, on thecontrary, a mechanism of response to external factors, which can affectany individual, even if individuals with so-called sensitive skin reactto them more quickly than do others. This mechanism is notimmunological.

The Applicant has now found that sensitive skins could be divided intotwo major clinical forms, irritable skins and intolerant skins.

An Irritable skin is a skin which reacts by pruritus, that is to say byitching or by prickling, to different factors such as the environment,emotions, foods, windy conditions, rubbing, shaving soap, surfactants,hard water with a high chalk concentration, temperature changes or wool.In general, these signs are associated with a dry skin with or withoutsores, or with a skin which displays erythema.

An intolerant skin is a skin which reacts by sensations of inflammationor of tightness, by pruritus, that is to say by itching or prickling, bytingling and/or red blotches, to different factors such as theenvironment, emotions and foods. In general, these signs are associatedwith erythema and with a skin with or without sores.

“Sensitive” scalps have a more unequivocal symptomatology: thesensations of pruritus and/or of prickling and/or of inflammation areessentially triggered by local factors such as rubbing, soap,surfactants, hard water with a high chalk concentration, shampoos oflotions. These sensations are also sometimes triggered by factors suchas the environment, emotions and/or foods. Erythema and hyperseborrhocaof the scalp as well as a dandruff state are frequently associated withthe above signs.

Moreover, in some anatomical regions, such as the major folds (inguinal,genital, axillary, popliteal, anal and inframammary regions, bend of theelbow) and the feet, sensitive skin manifests itself in pruriginoussensations and/or dysaesthetic sensations (inflammation, prickling)associated especially with sweating, with rubbing, with wool, withsurfactants, with hard water with a high chalk concentration and/or withtemperature changes.

To determine whether a skin is sensitive or otherwise, the Applicant hasalso developed a test. In effect, after performing a large number oftests with the object of defining a sensitive skin, it found,surprisingly, that there was a link between persons having sensitiveskin and those who reacted to a topical application of capsaicin.

The capsaicin test consists in applying 0.05 ml of a cream containing0.075% of capsaicin to approximately 4 cm² of skin, and noting theappearance of subjective signs caused by this application, such asprickling, burning and itching. In subjects having sensitive skins,these signs appear between 3 and 20 minutes after the application, andare followed by the appearance of an erythema which begins at theperiphery of the area of application.

Hitherto, capsaicin was used as a medicinal product, especially fortreating the pains of shingles. Capsaicin causes a release ofnouropeptides, and especially of tachykinins which originate from nerveendings of the epidemiis and the dermis. The Applicant found that thephysiopathological mechanism common to all the states of sensitive skinswas associated with a groat capacity to release tachykinins and moreespecially substance P in the skin. It is known, in addition, thatsubstance P released by epidermal sensory endings induces a cascade ofbiochemical events in which the first steps affect the mast calls. Thebinding of substance P to mast cell receptors induces a release ofnumerous pro-inflammatory mediators, among them histamine, serotonin,initerleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL8) andtumour necrosis factor alpha (TNF alpha).

Moreover, the Applicant found that sensitive skins as are defined aboveare, in addition, characterized by high levels of interleukin-1 and/orof histamine in the superficial layers of the epidermis. These levelsrise proportionately as the state of reactivity of the skin increases.

The Applicant has now discovered that the essential characteristics ofsensitive skins (irritation reactions and cutaneous intolerancereactions) are associated with the release of substance P andconsequently with the release of histamine, of interleukin-1 andparticularly of TNF alpha, and that interleukin-1 antagonists and/or TNFalpha antagonists and/or histamine antagonists may be used in thepreventive and/or curative treatment of sensitive skins.

Histaminc, interleukin-1 and/or TNF alpha “antagonists” are understoodto mean all substances capable of inhibiting the release and/orsynthesis and/or receptor binding of histamine, of interleukin-1 and/orof TNF alpha, respectively. The antagonists inhibiting the receptorbinding of histamine are agents specific for the type 1 histamine (H₁)receptor.

In addition, the Applicant found that the addition of interleukin-1antagonists and/or of TNF alpha antagonists to cosmetic, pharmaceuticalor dermatological compositions for topical application containingirritant products (alpha-hydroxy acids, retinoids, benzoyl peroxide,etc.) also enabled the irritation reactions usually caused by theseproducts to be decreased or even eliminated. These irritation reactionsmanifest themselves within moments following application, indysaesthetic sensations (inflammation, burning, itching or pruritussensations, prickling sensations, tightness, etc.), and/or in redblotches, and/or in oedema. These irritation stales may also manifestthemselves some time after application, in the persistence, appearanceor reappearance of the abovementioned dysaesthetic sensations and/or inred blotches and/or scales; these skin irritation states may assume theappearance of plaques of cutaneous xerosis and/or sores.

Moreover, histamine release induced by neurogenic inflammation causes avasodilatation which manifests itself in erythema, oedema and pruritus.Thus, the addition of histamine antagonists specific for the H₁receptors to irritant cosmetic, pharmaceutical or dermatologicalcompositions also enables the irritation reactions usually caused bythese products to be decreased or even eliminated.

To treat sensitive skins, the Applicant hence envisaged the use ofhistamine antagonists, interleukin-1 antagonists and/or TNF alphaantagonists. It found, in effect, surprisingly, that the incorporationof histamine antagonists, interleukin-1 antagonists and/or TNF alphaantagonists in a cosmetic, pharmaceutical or dermatological compositionenables the irritation and/or dysaesthetic sensations and/or pruritus ofthe skin and/or mucosae to be avoided.

Hence the subject of the present invention is the use of at least onecompound chosen from interteukin-1 antagonists, TNF alpha antagonistsand combinations thereof, in a composition containing a cosmetically,pharmaceutically or dermatologically acceptable medium, for treatingsensitive skins.

The subject of the present invention is also the use in a topicalcomposition of at least one compound chosen from interleukin-1antagonists, TNF alpha antagonists and combinations thereof, forpreventing and/or combating skin irritations and/or sores and/orerythema and/or sensations of inflammation and/or of dysaesthesia and/orpruritus and/or prickling and/or tingling and/or discomfort and/ortightness of the skin and/or mucosae.

According to the invention, the topical composition may contain, inaddition, a constituent chosen from histamine antagonists and andcombinations thereof.

The subject of the present invention is also the use in a topicalcomposition of at least one constituent chosen from histamineantagonists and combinations thereof, for preventing and/or combatingskin irritations and/or sores and/or sensations of inflammation and/orof dysaesthesia and/or prickling and/or tingling and/or discomfortand/or tightness of the skin and/or mucosae.

A cosmetically, dermatologically or pharmaceutically acceptable mediumis a medium which is compatible with the skin, scalp, nails and mucosae.The composition containing a histamine antagonist and/or aninterieukin-1 antagonist and/or a TNF alpha antagonist may hence beapplied to the face, neck, hair and nails, or any other area of the skinof the body such as the major folds (axillary or inframammary regions,bend of the elbow and the like).

For a substance to be recognized as a histamine, interleukin-1 (IL-1) orTNF alpha receptor antagonist, it must satisfy, in particular, thefollowing characteristic:

have a histamine, IL-1 or TNF alpha receptor antagonist pharmacologicalactivity, that is to say induce a coherent pharmacological response inat least one of the following tests:

for histamine receptor antagonists: an inhibition of tile contraction ofsmooth muscles induced by the administration of histamine;

for IL-1 receptor antagonists: inhibition of the IL-1-induced adhesionof macrophages to endothelial cells, or inhibition of the IL-1-inducedrelease of superoxide anions from neutrophils;

for TNF alpha receptor antagonists: inhibition of the TNF alpha-inducedadhesion of mactophages to endothelial cells, or inhibition of the TNFalpha-induced release of superoxide anions from neutrophils orinhibition of the mitogenic activity of TNF alpha with respect to thefibroblasts of the dermis.

The histamine, intcrleukin-1 (IL-1) or TNF alpha antagonist may, inaddition, have a selective affinity for the specific receptors for thesecompounds: H₁, IL-1 and TNF alpha.

For a substance to be recognized as an antagonist of the release and/orsynthesis of histamine, of interleukin-1 or of TNF alpha, it mustsatisfy, in particular, the following characteristic:

inhibition of histamine release by mast cells stimulated with thecompound 48/80 or stimulated with a calcium ionophore (A23 187)

inhibition of the release of interleukin-1 or of TNF alpha by monocytes(U937 cells) differentiated with a phorbol ester (PMA).

Hitherto, histamine antagonists were used to treat allergic disorderssystemically. Interleukin-1 antagonists are currently being tested incertain chronic inflammatory disorders such as rheumatic disorders,septic shock, asthma, psoriasis and ocular allergies. TNF alphaantagonists are currently being tested for treating fever, septic shockand cachexia.

The antagonists of the invention are, in particular, compoundscomprising at least one heterocycle and nitrogen compounds comprising atleast one benzene ring.

The histamine II₁ receptor antagonists which can be used in theinvention are those traditionally used in the treatment of allergic andanaphylactic states, as well as those for combating travel sickness.These compounds can be, for example, diethylenediaminc derivatives suchas cinnarizine, cyclizine; aminopropane derivatives such asdexchlorpheniramine, triprolidine; phenothiazine derivatives such aspromethazine, alimemazine; and also the compounds mentioned on pages 116to 118 of the book by Joseph R. Prous, The Year's Drug News, TherapeuticTargets, 1994 edition, Prous Science Publishers, such as cetirizine HCl,ebastinc, loratadine, setastine HCl.

The histamine release inhibitors are, in particular, oxygen- orsulphur-containing heterocyclic compounds such as furan derivatives,benzofuran derivatives, thiophene derivatives and benzothiophenederivatives, optionally containing nitrogenous substituents, such asthose described in the documents U.S. Pat. NO. 4,931,459, U.S. Pat. No.4,910,317 and EP-A-299,457, and more especially alkoxy- and/oraryloxytetrazolylbenzofurancarboxamides or alkoxy- and/oraryloxytetrazolylbenzothiophenecarboxamides. By way of example,5-methoxy-3-phenoxy-N-(1H-tetrazol-5yl)benzothiophene-2-carboxamide,5-methoxy-3-(1-methylethoxy)-N-(1H-tetrazol-5-yl)benzothiophene-2-carboxamide,6methoxy-3-(1-methylethoxy)-N-(1H-tetrazol-5-yl)benzothiophenc-2-carboxamide,5methoxy-3-(1-methylethyl)-N-(1H-tetrazol-5-yl)benzothiophene-2-carboxamide,3benzyloxy-5-methoxy-N-(1H-tetrazol-5-yl)benzothiophene-2-carboxamrideand 5-methoxy-3-phenoxy-N-(1H-tetrazol-5yl)benzothiophene-2-carboxamidemay be mentioned.

An interieukin-1 release antagonist which can be used in the inventioncan be auranofin or SKF-105809(6,7-dihydro-2-[4-(methylsulfinyl)phenyl]-3-)4-pyridinyl)-5Hh-pyrrolo[1,2-a]imidazole.An interleukin-1 synthesis antagonist can be lactoferin.

The TNF alpha receptor antagonists and the inhibitors of TNF alpharelease and/or synthesis which can be used in the invention are, inparticular, lisophyline, A802715 and sulphasalazine. A-802715 is axanthine derivative available from Hoechst which inhibits both TNFrelease and TNF action having the following structure:

The histamine antagonists, interleukin-1 antagonists and TNF alphaantagonists may be synthesized or extracted from natural products (plantor animal).

In the compositions according to the invention, the histamineantagonists, interieukin-1 antagonists and/or TNF alpha antagonists arepreferably used in an amount ranging from 0.000001 to 5% by weightrelative to the total weight of the composition, and especially in anamount ranging from 0.0001 to 0.1% by weight relative to the totalweight of the composition.

The compositions according to the invention may be presented in allpharmaceutical dosage forms normally used for topical application, inparticular in the form of aqueous, aqueous-alcoholic or oily solutions,of dispersions of the lotion or serum type, of anhydrous or lipophilicgels, of emulsions of liquid or semi-solid consistency of the milk type,obtained by dispersing a fatty phase in an aqueous phase (O/W) or viceversa (W/O), or of suspensions or emulsions of soft, semi-solid or solidconsistency of the cream or gel type, or alternatively ofmicroemulsions, of microcapsules, of microparticies or of vesiculardispersions of the ionic and/or nonionic type. These compositions areprepared according to standard methods.

They may also be used for the scalp in the form of aqueous, alcoholic oraqueous-alcoholic solutions, or in the form of creams, gels, emulsionsor foams or alternatively in the form of aerosol compositions alsocontaining a propellent agent under pressure.

The amounts of the different constituents of the compositions accordingto the invention are those traditionally used in the fields in question.

These compositions constitute, in particular, cleansing, protective,treatment or skin care creams for the face, hands, feet, majoranatomical folds or the body (for example day creams, night creams,make-up removal creams, foundation creams, sun-protection creams), fluidfoundations, make-up removal milks, protective or skin care body milks,sun-protection or, better still, after-sun milks, skin care lotions,gels or foams, such as cleansing or disinfecting lotions, sun-protectionlotions, artificial tanning lotions, bath compositions, deodorantcompositions containing a bactericidal agent, aftershave gels orlotions, depilatory creams, compositions for treating insect bites, painrelief compositions or compositions for treating certain skin disorderssuch as those mentioned above.

The compositions according to the invention may also consist of solidpreparations constituting cleansing bars or soaps.

The compositions may also be packaged in the form of an aerosolcomposition also containing a propellent agent under pressure.

The histamine antagonists, interleukin-1 antagonists and/or TNF alphaantagonists may also be incorporated in various hair care or treatmentcompositions, and in particular shampoos, where appropriateantiparasitic, setting lotions, treatment lotions, styling creams orgels, dyeing (normally oxidation dyeing) compositions, where appropriatein the form of colouring shampoos, hair restructuring lotions,peronanent-waving compositions (in particular compositions for the firststage of permanent waving), lotions or gels for combating hair loss, andthe like.

The compositions of the invention may also be for dentibuccal use, forexample a toothpaste or a mouthwash. In this case, the compositions cancontain standard adjuvants and additives for compositions for buccaluse, and in particular surfactants, thickening agents, humectant agents,polishing agents such as silica, various active ingredients such asfluorides, especially sodium fluoride, and, where appropriate,sweetening agents such as saccharin sodium.

When the composition of the invention is an emulsion, the proportion ofthe fatty phase can range from 5% to 80% by weight, and preferably from5% to 50% by weight, relative to the total weight of the composition.The oils, emulsifiers and coemulsifiers used in the composition inemulsion form are chosen from those traditionally used in the cosmetics,pharmaceutical or dermatological fields. The emulsifier and thecoemulsifier are present in the composition in a proportion ranging from0.3% to 30% by weight, and preferably from 0.5 to 30% or, better still,from 0.5 to 20%, by weight relative to the total weight of thecomposition. The emulsion can, in addition, contain lipid vesicles.

When the composition of the invention is an oily gel or solution, thefatty phase can represent more than 90% of the total weight of thecomposition.

In a known manner, the composition of the invention may also containadjuvants which are customary in the cosmetics, pharmaceutical ordermatological field, such as hydrophilic or lipophilic gelling agents,hydrophilic or lipophilic active agents, preservatives, antioxidants,solvents, perfumes, fillers, screening agents, bactericides, odourabsorbers and colouring matter. The amounts of these different adjuvantsare those traditionally used in the cosmetic, pharmaceutical ordermatological field, and are, for example, from 0.01% to 10% of thetotal weight of the composition. These adjuvants, depending on theirnature, may be introduced into the fatty phase, into the aqueous phaseand/or into lipid spherules.

As oils which can be used in the invention, mineral oils (liquidparaffin), vegetable oils (liquid fraction of shea butter, sunfloweroil), animal oils (perhydrosqualene), synthetic oils (Purceilin oil),silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers) may be mentioned. Fatty alcohols, fatty acids (stearic acid)and waxes (paraffin, carnauba, beeswax) may also be used as fattysubstances.

As emulsifiers which can be used in the invention, glyceryl stearate,polysorbate 60 and the PEG-6/PEG-32/glycol stearate mixture sold underthe name Tefose® 63 by the company Gattefosse may be mentioned asexamples.

As solvents which can be used in the invention, lower alcohols, inparticular ethanol and isopropanol, and propylene glycol may bementioned.

As hydrophilic gelling agents, carboxyvinyl polymers (carbomer), acryliccopolymers such as acrylate/alkylacrylate copolymers, polyacrylamides,polysaccharides such as hydroxypropylcellulose, clays and natural gumsmay be mentioned, and as lipophilic gelling agents, modified clays suchas bentones, metal salts of fatty acids such as aluminum stearates andhydrophobic silica, or alternatively ethylcellulose and polyethylene maybe mentioned.

As hydrophilic active agents, proteins or protein hydfolysotes, aminoacids, polyols, urea, allantoin, sugars and sugar derivatives,water-soluble vitamins, starch and plant extracts, in particular thoseof Aloe vera may be used.

As lipophilic active agents, retinol (vitamin A) and its derivatives,tocopherol (vitamin E) and its derivatives, essential fatty acids,ceramides and essential oils may be used.

The histamine antagonists, interleukin-1 antagonists and/or TNF alphaantagonists may, inter alia, be combined with active agents intended, inparticular, for preventing and/or treating skin complaints. Among theseactive agents, there may be mentioned, by way of example:

agents which modulate differentiation and/or proliferation and/or skinpigmentation, such as retinoic acid and its isomers, retinol and itsesters, vitamin D and its derivatives, oestrogens such as oestradiol,kojic acid or hydroquinone;

antibacterials such as clindamycin phosphate, erythromycin orantibiotics of the tetracyclin class;

antiparasitics, especially metronidazole, crotamiton or pyrethrinoids;

antifungals, especially compounds belonging to the imidazol class suchas econazole, ketoconazole or miconazole or their salts, polyenecompounds such as amphotericin B, compounds of the allylamine familysuch as terbinafine, or alternatively octopirox;

steroidal anti-inflammatory agents such as hydrocortisone, betamethasonevalerate or clobetasol propionate, or non-steroidal anti-inflammatoryagents such as ibuprofen and its salts, diclofenac and its salts,acetylsalicylic acid, acetaminophen or glycyrrhetinic acid;

anaesthetic agents such as lidocaine hydrochloride and its derivatives;

antipruriginous agents such as thenalidine, trimeprazine orcyproheptadine;

antiviral agents such as acyclovir;

keratolytic agents such as alpha- and beta-hydroxycarboxylic or betaketocarboxylic acids, their salts, amides or esters, and more especiallyalpha-hydroxy acids such as glycolic acid, lactic acid, tartaric acid,citric acid and, generally speaking, the fruit acids, and beta-hydroxyacids such as salicylic acid and its derivatives, in particular itsalkylated derivatives such as 5-n-octanoylsalicylic acid;

free-radical scavenging agents such as alpha-tocopherol or its esters,superoxide dismutases, some metal chelators or ascorbic acid and itsesters;

antisoborrhocic agents such as progesterone;

antidandruff agents such as octopirox or pyrithione zinc;

anti-acne agents such as retinoic acid or benzoyl peroxide.

Advantageously, the histamine antagonists, interleukin-1 antagonistsand/or TNF alpha antagonists are combined with products having anirritant side-effect, and in particular active agents commonly used inthe cosmetics, pharmaceutical or dermatological field. The presence of ahistamine antagonist, an interleukin-1 antagonist and/or a TNF alphaantagonist in a cosmetic, pharmaceutical or dermatological compositioncontaining a product or even an active agent having an irritant effectenables this irritant effect to be greatly attenuated or eveneliminated.

In particular, the histamine antagonist, interleukin-1 antagonist and/orTNF alpha antagonist make it possible, in particular, to increase theamount of cosmetic, pharmaceutical or dermatological active agentrelative to the amount normally used, with a view to improved efficacy.

Thus, the subject of the invention is also a composition containing, ina cosmetically, pharmaceutically or dermatologically acceptable medium,at least one product having an irritant side-effect, characterized inthat it contains at least one agent antagonistic to this effect, chosenfrom interleukin-1 antagonists, TNF alpha antagonists and combinationsthereof.

The subject of the invention is also the use, in a topical compositioncontaining a cosmetically, pharmaceutically or dermatologicallyacceptable medium and at least one product having an irritantside-effect, of at least one compound chosen from histamine antagonists,interleukin-1 antagonists, TNF alpha antagonists and combinationsthereof, for eliminating this irritant effect.

The irritant products to which the invention applies are, in particular,perfumes, surfactants (ionic or nonionic), preservatives, some sunscreenagents, organic solvents, alcoholic solutions and some cosmetic,pharmaceutical or dermatological active agents.

In particular, the active agents having an irritant side-effet arechosen from α-hydroxy acids (glycolic, lactic, malic, citric, tartaric,mandelic), β-hydroxy acids (salicylic acid and its derivatives), α-ketoacids, β-keto acids, retinoids (retinol and its esters, retinal,retinoic acid and its derivatives, retinoids, in particular thosedescribed in the documents HR-A-2,570,377, EP-A-199,636, EP-A-325,540,EP-A-402072), anthralins (dioxyanthranol), anthranoids, peroxides (inparticular benzoyl perdxide), minoxidil, lithium salts, antimetabolites,vitamin D and its derivatives, hair dyes or colorants(para-phenylenediamine and its derivatives, aminophenols), alcoholicperfuming solutions (perfumes, toilet water, aftershave, deodorants),antiperspirant agents (some aluminium salts), depilatory orpermanent-waving active agents (thiols), depigmenting agents(hydroquinone) and delousing active agents (pyrethrin).

The use of a histamine antagonist, interleukin-1 antagonist and/or TNFalpha antagonist makes it possible, in particular, to multiply from 2-to 10-fold the amount of product, and more especially of active agent,having an irritant side-effect, relative to the prior state of the art,without all the unpleasant sensations mentioned above being experienced.Thus, it is possible to use hydroxy acids up to 50% of the weight of thecomposition or retinoids up to 5%, without any discomfort.

In particular, the composition contains one or more histamineantagonists, one or more intcrieukin-1 antagonists and/or one or moreTNF alpha antagonists chosen from alkoxy- and/oraryloxytetrazolylbenzofurancarboxamides or an alkoxy- and/oraryloxytetrazolylbenzothiophenecarboxamides and one or more activeagents having an irritant side-effect, chosen from alpha-hydroxy acidsand beta-hydroxy acids.

The subject of the present invention is, in addition, a cosmetictreatment process, characterized in that a composition as describedabove, containing at least one TNF alpha antagonist in a cosmeticallyacceptable medium is applied to the skin, to the scalp and/or to themucosae.

The cosmetic treatment process of the invention may be carried out, inparticular, by applying the hygiene or cosmetic compositions as aredefined above according to the customary technique for using thesecompositions. For example: application of creams, gels, serums, lotion,make-up removal milks or after-sun compositions to the skin or to dryhair, application of a hair lotion to wet hair or of shampoos, oralternatively application of dentifrice to the gums.

The examples which follow illustrate the invention. In these examples,the proportions shown are percentages by weight.

EXAMPLE 1

Make-up Removal Lotion for the Face

Loratidine 0.05 Antioxidant 0.05 Isopropanol 40.00 Preservative 0.30Water qs 100%

EXAMPLE 2

Make-up Removal Lotion for the Face

Cetirizine 0.001 Antioxidant 0.05 Isopropanol 40.00 Preservative 0.30Water qs 100%

EXAMPLE 3

Face Care Gel

Auranofin 0.05 Hydroxypropylcellulose (Klucel H 1.00 sold by the companyHercules) Antioxidant 0.05 Isopropanol 40.00 Preservative 0.30 Water qs100%

EXAMPLE 4

Face Care Gel

Lisophyline 0.04 Hydroxypropylcellulose (Klucel H 1.00 sold by thecompany Hercules) Antioxidant 0.05 Isopropanol 40.00 Preservative 0.30Water qs 100%

EXAMPLE 5

Face Care Cream (Oil-in-water Emulsion)

Sulphasalazine 0.02 Glyceryl stearate 2.00 Polysorbate 60 (Tween 60 soldby the 1.00 company ICI) Stearic acid 1.40 Triethanolamine 0.70 Carbomer0.40 Liquid fraction of shea butter 12.00 Perhydrosqualene 12.00Antioxidant 0.05 Perfume 0.5 Preservative 0.30 Water qs 100%

EXAMPLE 6

Treatment Shampoo

Loratadine 0.02 Hydroxypropylcellulose (Klucel H sold by the companyHercules) 1.00 Perfume 0.50 Preservative 0.30 Water qs 100%

EXAMPLE 7

Antiwrinkle Skin Care Cream for the Face (Oil-in-water Emulsion)

Cetirizine 0.15 Glyceryl stearate 2.00 Polysorbate 60 (Tween 60 sold bythe 1.00 company ICI) Stearic acid 1.40 5-n-Octanoylsalicylic acid 0.50Triethanolamine 0.70 Carbomer 0.40 Liquid fraction of shea butter 12.00Perhydrosqualene 12.00 Antioxidant 0.05 Perfume 0.50 Preservative 0.30Water qs 100%

EXAMPLE 8

Emulsified Gel for Treating Insect Bites (Oil-in-water Emulsion)

Cyclomethicone 3.00 Purcellin oil (sold by the company 7.00 Dragoco)PEG-6/PEG-32/glycol stearate 0.30 (Tefose ® 63 from Gattefosse)Setastine 0.02 Preservative 0.30 Perfume 0.40 Carbomer 0.60 Crotamiton5.00 Glycyrrhetinic acid 2.00 Ethyl alcohol 5.00 Triethanolamine 0.20Water qs 100%

EXAMPLE 9

Pain Relief Gel

Cetirizine 0.03 Hydroxypropylcellulose (Klucel H 1.00 sold by thecompany Hercules) Antioxidant 0.05 Lidocaine hydrochloride 2.00Isopropanol 40.00 Preservative 0.30 Water qs 100%

EXAMPLE 10

Cream for Treating Solar Erythema (Oil-in-water Emulsion)

Dexchlorpheniramine 0.25 Glyceryl stearate 2.00 Polysorbate 60 (Tween 60sold by the 1.00 company ICI) Stearic acid 1.40 Glycyrrhetinic acid 2.00Triethanolamine 0.70 Carbomer 0.40 Liquid fraction of shea butter 12.00Sunflower oil 10.00 Antioxidant 0.05 Perfume 0.5 Preservative 0.30 Waterqs 100%

EXAMPLE 11

Antiwrinkle Skin Care Cream for the Face (Oil-in-water Emulsion)

This example differs from Example 7 by the replacement of cetirizine by3-benyloxy-5-methoxy-N-(1H-tetrazol-5-yl)benzothiophene-2-carboxamidc,manufactured according to Example 1 of the document EP-A-299,457, and5-n-octanoylsalicylic acid by glycolic acid.

EXAMPLE 12

Antiwrinkle Skin Care Cream for the Face (Oil-in-water Emulsion)

This example differs from Example 7 by the replacement of sulphasalazineby 5-methoxy-3-phenoxy-N-(1H-tetrazol-5-yl)benzothiophene-2-carboxamide,manufactured according to Example 2 of the document EP-A-299,457, and5-n-octanoylsalicylic acid by a fruit acid mixture (lactic, glycolic,tartaric, citric and malic acids).

EXAMPLE 13

Gel for Treating Acne

all-trans-Retinoic acid 0.05 Loratidine 0.55 Hydroxypropylcellulose(Klucel H 1 sold by the company Hercules) Antioxidant 0.05 Isopropanol40 Preservative 0.3 Water qs 100%

What is claimed is:
 1. A method for the treatment of sensitive skin inan individual having sensitive skin in need of said treatment, saidmethod comprising administering to said individual a composition adaptedfor the treatment of sensitive skin comprising at least one compoundselected from the group consisting of interleukin-1 antagonists, TNFalpha antagonists and combinations thereof, in an amount effective totreat sensitive skin, and a cosmetically, dermatologically orpharmaceutically acceptable medium, said compound being capable ofinhibiting the IL-1-induced adhesion of macrophages to endothelialcells, inhibiting the IL-1-induced release of superoxide anions fromneutrophils, inhibiting the TNF alpha-induced adhesion of macrophages toendothelial cells, inhibiting the TNF alpha-induced release ofsuperoxide anions from neutrophils, inhibiting the mitogenic activity ofTNF alpha by dermal fibroblasts, or inhibiting the release ofinterleukin-1 or TNF alpha by phorbol ester induced differentiatedmonocytes.
 2. The method of claim 1, wherein the compound is selectedfrom the group consisting of auranofin, SKF-105809, lactoferin,lisophyline, A802715, sulphasalazine and combinations thereof.
 3. Themethod of claim 1, wherein the composition further comprises at leastone histamine antagonist, said histamine antagonist being capable ofinhibiting the contraction of smooth muscles induced by theadministration of histamine or inhibiting the release of histamine bystimulated mast cells.
 4. The method of claim 3, wherein the histamineantagonist is a heterocycle or a nitrogen compound containing at leastone benzene ring.
 5. The method of claim 1, wherein the amount of thecompound ranges from about 0.000001 to 5% by weight relative to thetotal weight of the composition.
 6. The method of claim 1, wherein theamount of the compound ranges from about 0.0001 to 0.1% by weightrelative to the total weight of the composition.
 7. The method of claim1, wherein the cosmetically, pharmaceutically, or dermatologicallyacceptable medium comprises an aqueous, oil or aqueous alcoholicsolution, a water-in-oil emulsion, an oil-in-water emulsion, amicroemulsion, an aqueous gel, an anhydrous gel, a serum, or adispersion of vesicles, microcapsules or microparticles.
 8. The methodof claim 1, wherein the composition further comprises at least one agentselected from the group consisting of anti-bacterial, antiparasitic,antifungal, anti-inflammatory, antipruriginous, anaesthetic, antiviral,keratolytic, free-radical scavenging, antiseborrhoeic, antidandruff andanti-acne agents and/or agents which modulate the differentiation and/orthe proliferation and/or the pigmentation of skin.
 9. The method ofclaim 8, wherein the agent is selected from the group consisting oflidocaine hydrochloride, antiparasitic agents and non-steroidalanti-inflammatory agents.
 10. A method for the treatment of irritableskin or the prevention of one or more manifestations of irritable skinin an individual having irritable skin in need of said treatment orprevention, said method comprising topically administering to saidindividual a composition adapted for the treatment of irritable skincomprising at least one compound selected from the group consisting ofinterleukin-1 antagonists, TNF alpha antagonists and combinationsthereof, in an amount effective to treat irritable skin or to preventone or more manifestations of irritable skin, and a cosmetically,dermatologically or pharmaceutically acceptable medium, said compoundbeing capable of inhibiting the IL-1-induced adhesion of macrophages toendothelial cells, inhibiting the IL-1-induced release of superoxideanions from neutrophils, inhibiting the TNF alpha-induced adhesion ofmacrophages to endothelial cells, inhibiting the TNF alpha-inducedrelease of superoxide anions from neutrophils, inhibiting the mitogenicactivity of TNF alpha by dermal fibroblasts, or inhibiting the releaseof interleukin-1 or TNF alpha by phorbol ester induced differentiatedmonocytes.
 11. The method of claim 10, wherein said treatment orprevention is treating or preventing at least one of the following: (i)sores; (ii) erythema; (iii) dysesthetic sensations; (iv) sensations ofinflammation; (v) pruritus; (vi) prickling; (vii) tingling; (viii)discomfort; and (ix) tightness of the skin, and/or mucosae.
 12. Themethod of claim 10, wherein the topically administered compositionadditionally comprises at least one histamine antagonist, said histamineantagonist being capable of inhibiting the contraction of smooth musclesinduced by the administration of histamine or inhibiting the release ofhistamine by stimulated mast cells.
 13. The method of claim 10, whereinthe amount of the compound ranges from about 0.000001 to 5% by weightrelative to the total weight of the composition.
 14. The method of claim12, wherein the amount of the histamine antagonist ranges from about0.000001 to 5% by weight relative to the total weight of thecomposition.
 15. The method of claim 10, wherein the amount of thecompound ranges from about 0.0001 to 0.1% by weight relative to thetotal weight of the composition.
 16. The method of claim 12, wherein theamount of the histamine antagonist ranges from about 0.0001 to 0.1% byweight relative to the total weight of the composition.
 17. A method forthe treatment of irritable skin or the prevention of one or moremanifestations of irritable skin in an individual having irritable skinin need of said treatment or prevention, said method comprisingtopically administering to said individual a composition adapted for thetopical treatment of irritable skin or the prevention of one or moremanifestations of irritable skin comprising at least one histamineantagonist, in an amount effective to treat irritable skin or to preventone or more manifestations of irritable skin, and a cosmetically,dermatologically or pharmaceutically acceptable medium, said histamineantagonist being capable of inhibiting the contraction of smooth musclesinduced by the administration of histamine or inhibiting the release ofhistamine by simulated mast cells.
 18. The method of claim 17, whereinsaid treatment or prevention is treating or preventing one of thefollowing: (i) sores; (ii) erythema; (iii) dysesthetic sensations; (iv)sensations of inflammation; (v) pruritus; (vi) prickling; (vii)tingling; (viii) discomfort; and (ix) tightness of the skin and/ormucosae.
 19. The method of claim 17, wherein the amount of the histamineantagonist ranges from about 0.00001 to 5% by weight relative to thetotal weight of the composition.
 20. The method of claim 17, wherein theamount of the histamine antagonist ranges from about 0.0001 to 0.1% byweight relative to the total weight of the composition.
 21. A method ofcosmetic treatment in an individual having sensitive skin in need ofsaid treatment, said method comprising applying to the skin, scalp,lips, mucosae or nails a topically administrable composition comprisingat least one TNF alpha antagonist compound, in an amount effective totreat sensitive skin, and a cosmetically acceptable medium, saidcompound being capable of inhibiting the TNF alpha-induced adhesion ofmacrophages to endothelial cells, inhibiting the TNF alpha-inducedrelease of superoxide anions from neutrophils, inhibiting the mitogenicactivity of TNF alpha by dermal fibroblasts, or inhibiting the releaseof TNF alpha by phorbol ester induced differentiated monocytes.
 22. Themethod of claim 21, wherein the amount of the compound ranges from about0.000001 to 5% by weight relative to the total weight of thecomposition.
 23. The method of claim 21, wherein the amount of thecompound ranges from about 0.0001 to 0.1% by weight relative to thetotal weight of the composition.
 24. A method of cosmetic treatment inan individual having sensitive skin in need of said treatment, saidmethod comprising applying to the skin, scalp, lips, mucosa, or nails, acosmetically administrable composition comprising at least one TNF alphaantagonist or interleukin-1 antagonist, in an amount effective to treatsensitive skin, and a cosmetically acceptable medium, said TNF alphaantagonist or interleukin-1 antagonist being capable of inhibiting theIL-1-induced adhesion of macrophages to endothelial cells, inhibitingthe IL-1-induced release of superoxide anions from neutrophils,inhibiting the TNF alpha-induced adhesion of macrophages to endothelialcells, inhibiting the TNF alpha-induced release of superoxide anionsfrom neutrophils, inhibiting the mitogenic activity of TNF alpha bydermal fibroblasts, or inhibiting the release of interleukin-1 or TNFalpha by phorbol ester induced differentiated monocytes.
 25. The methodof claim 24, wherein said cosmetic composition comprises both a TNFalpha antagonist and an interleukin-1 antagonist.
 26. The method ofclaim 24, wherein said cosmetic composition comprises at least one TNFalpha antagonist.
 27. The method of claim 24, wherein said cosmeticcomposition comprises at least one interleukin-1 antagonist.
 28. Themethod of claim 24, wherein the amount of said compound ranges from0.000001 to 5% by weight relative to the weight of the composition. 29.The method of claim 28, wherein the amount of said compound ranges from0.0001 to 0.1% by weight relative to the total weight of thecomposition.
 30. The method of claim 24, wherein said compositioncomprises a formulation selected from the group consisting of a cream,gel, serum, lotion, make-up removal, milk, after-sun composition, anddentifrice.